Host: The Japanese Society of Toxicology
Name : The 47th Annual Meeting of the Japanese Society of Toxicology
Date : 2020 -
[Purpose] MicroRNAs (miRNA) have received much attention as potential biomarkers of drug-induced liver injury. We recently reported that plasma miR-143-3p and miR-218a-5p were increased in the early stage of severe cholestasis in rats. In this study, we investigated whether these miRNAs increase in a severity-dependent manner and pathophysiological roles of them.
[Method] Male SD rats were orally administered different doses of 4,4-methylenedianiline or α-naphthylisothiocyanate to induce cholestasis. Rats were also orally administered acetaminophen or thioacetamide to induce hepatocellular injury. The miRNA expression levels were measured by RT-qPCR. Effects of miR-218a-5p on proliferation were investigated in an immortalized human cholangiocyte line MMNK-1. Target genes of miR-218a-5p were predicted by in silico analysis, and expression levels of target mRNAs after overexpression of miR-218-5p were determined.
[Result and discussion] Plasma miR-218a-5p and miR-143-3p levels were dose-dependently increased in cholestatic rats. Proliferation of MMNK-1 cells was significantly suppressed after overexpression of miR-218a-5p. The mRNA levels of GNAI2, PPP1CB and PPP2R5A, which were potential targets, were decreased by overexpression of miR-218a-5p in MMNK-1 cells. In conclusions, our data suggest that 1) miR-218a-5p decreases cholangiocyte proliferation by inhibiting the expression of GNAI2, PPP1CB and PPP2R5A thereby associated with pathogenesis of cholestasis; and 2) miR-218a-5p was leaked into plasma probably from damaged cholangiocytes in a severity-dependent manner.
